1. Field of the Invention
The present invention generally relates to the fields of medicinal and synthetic chemistry. Specifically, the invention relates to the synthesis and use of water-soluble and water-dispersible carotenoids, including analogs, derivatives, and intermediates thereof, as therapeutic and/or prophylactic anti-inflammatory and anti-oxidant agents that reduce tissue damage associated with inflammation.
2. Description of the Related Art
Inflammation plays an important role in the pathophysiology of ischemic heart disease (Yeh et al., 2001). Elevated levels (>2 mg/dl) of C-reactive protein concentration (CRP), commonly used as a marker for an acute inflammatory response, are correlated with increased mortality due to cardiovascular events (Lagrand et al., 1999).
This relationship holds true for asymptomatic individuals (Ridker et al., 2000) and patients with unstable angina
(Lindahl et al., 2000) and acute myocardial infarction (Pietila et al., 1996). It has been suggested that the epidemiological studies relating CRP to the incidence and outcome of ischemic syndromes are not simply due to CRP being a nonspecific marker of disease susceptibility or inflammation but rather that CRP might be involved directly in the pathogenesis of ischemic syndromes through a proinflammatory effect mediated by complement activation (Beranek, 1997). The primary evidence for this hypothesis is derived from studies of autopsy specimens showing co-localization of CRP with activated complement components in infarcted myocardial tissue but not in healthy myocardium (Lagrand et al., 1997; Yasojima et al., 1998b). Deposition of CRP also occurs in the ischemic rabbit myocardium (Kushner et al., 1963) and is closely correlated with the infiltration of polymorphonuclear leukocytes (pro-inflammatory cells) to the ischemic tissue (du Clos et al., 1981). Additionally, studies have shown that the endogenous increase in plasma CRP secondary to a remote inflammatory lesion is associated with an increase in myocardial tissue injury secondary to regional ischemia and reperfusion. The myocardial injury occurs via a complement-dependent mechanism, and can be ameliorated by pretreatment with heparin, N-acetylheparin or can be prevented in rabbits deficient in complement protein C6, which are incapable of forming the membrane attack complex (Barrett et al., 2002). The evolving paradigm suggests that in the normal, healthy adult any elevations of CRP in the absence of acute infection or acute tissue injury can potentially be deleterious; indeed, in umbilical cord blood levels are very low (<0.01 mg/dl). For example, cardiovascular patients at risk for inflammatory heart disease benefit from lowering of circulating CRP levels, without evidence of a “no effect level” for this marker (Ridker et al. 2005). Local production of CRP by cells of other than hepatic origin has now been convincingly demonstrated (Venugopal et al. 2005), suggesting a tissue-specific role for this acute phase protein. Previous studies have also shown that administering carotenoid analogs or derivatives can reduce the serum concentration of CRP following ischemic reperfusion injury (Publication No. US-2005-0009758 and PCT International Application Number PCT/US2003/023706). Therapies aimed at (1) reducing circulating levels of CRP in mammals; (2) in the localized and/or systemic production of CRP by liver and other tissues; and (3) the deposition of CRP (either with or without other endogenous inflammatory mediators) in pathological injury will have important therapeutic value (Ridker 2005).
Carotenoids are a group of natural pigments produced principally by plants, yeast, and microalgae. The family of related compounds now numbers greater than 700 described members, exclusive of Z and E isomers. Humans and other animals cannot synthesize carotenoids de novo and must obtain them from their diet. All carotenoids share common chemical features, such as a polyisoprenoid structure, a long polyene chain forming the chromophore, and near symmetry around the central double bond. Tail-to-tail linkage of two C20 geranyl-geranyl diphosphate molecules produces the parent C40 carbon skeleton. Carotenoids without oxygenated functional groups are called “carotenes”, reflecting their hydrocarbon nature; oxygenated carotenes are known as “xanthophylls.” Cyclization at one or both ends of the molecule yields 7 identified end groups (illustrative structures shown in FIG. 1). Examples of uses of carotenoid derivatives and analogs are illustrated in U.S. patent application Ser. No. 10/793,671 filed on Mar. 4, 2004, entitled “CAROTENOID ETHER ANALOGS OR DERIVATIVES FOR THE INHIBITION AND AMELIORATION OF DISEASE” by Lockwood et al. published on Jan. 13, 2005, as Publication No. US-2005-0009758 and PCT International Application Number PCT/US2003/023706 filed on Jul. 29, 2003, entitled “STRUCTURAL CAROTENOID ANALOGS FOR THE INHIBITION AND AMELIORATION OF DISEASE” by Lockwood et al. (International Publication Number WO 2004/011423 A2, published on Feb. 5, 2004) both of which are incorporated by reference as though fully set forth herein.
Documented carotenoid functions in nature include light harvesting, photoprotection, and protective and sex-related coloration in microscopic organisms, mammals, and birds, respectively. A relatively recent observation has been the protective role of carotenoids against age-related diseases in humans as part of a complex antioxidant network within cells. This role is dictated by the close relationship between the physicochemical properties of individual carotenoids and their in vivo functions in organisms. The long system of alternating double and single bonds in the central part of the molecule (delocalizing the π-orbital electrons over the entire length of the polyene chain) confers the distinctive molecular shape, chemical reactivity, and light-absorbing properties of carotenoids. Additionally, isomerism around C═C double bonds yields distinctly different molecular structures that may be isolated as separate compounds (known as Z (“cis”) and E (“trans”), or geometric, isomers). Of the more than 700 described carotenoids, an even greater number of the theoretically possible mono-Z and poly-Z isomers are sometimes encountered in nature. The presence of a Z double bond creates greater steric hindrance between nearby hydrogen atoms and/or methyl groups, so that Z isomers are generally less stable thermodynamically, and more chemically reactive, than the corresponding all-E form. The all-E configuration is an extended, linear, and rigid molecule. Z-isomers are, by contrast, not simple, linear molecules (the so-called “bent-chain” isomers). The presence of any Z in the polyene chain creates a bent-chain molecule. The tendency of Z-isomers to crystallize or aggregate is much less than all-E, and Z isomers may sometimes be more readily solubilized, absorbed, and transported in vivo than their all-E counterparts. This has important implications for enterable (e.g., oral) and parenteral (e.g., intravenous, intra-arterial, intramuscular, intraperitoneal, intracoronary, and subcutaneous) dosing in mammals.
Problems related to the use of some prior art carotenoids and structural carotenoid analogs or derivatives include: (1) the complex isomeric mixtures, including non-carotenoid contaminants, provided in natural and synthetic sources leading to costly increases in safety and efficacy tests required by such agencies as the FDA; (2) limited bioavailability upon administration to a subject; and (3) the differential induction of cytochrome P450 enzymes (this family of enzymes exhibits species-specific differences which must be taken into account when extrapolating animal work to human studies). Selection of the appropriate analog or derivative and isomer composition for a particular application increases the utility of carotenoid analogs or derivatives for the uses defined herein.
New methods of reducing or inhibiting one or more of the pathological complications associated with inflammation and/or tissue injury associated with inflammation, including deposition of pro-inflammatory molecules and protein complexes in a body tissue of a subject would be useful therapeutic agents. Carotenoid analogs or derivatives displaying properties of increased water-dispersibility and bioavailability would be beneficial for such applications.